Growth hormone (GH) is essential for normal longitudinal growth and metabolic homeostasis in children. While GH is itself an anabolic hormone, it is believed that most of its activity is mediated by the stimulation of insulin-like growth factors (IGF) or somatomedins. The complex hormonal regulation of GH secretion includes stimulatory (GH-releasing factor, GRF) and inhibitory (somatostatin) hypothalamic control as well as long loop feedback inhibition by the somatomedin peptides. The role of feedback inhibitor would be a unique action for the somatomedins whose major defined physiologic function is that of an anabolic growth factor. Moreover, the presence of insulin receptors on somatotrophic cells suggests that insulin may also play an important direct role in GH homeostasis. This grant will explore 2 major themes in the control of GH synthesis and release using continuous cell culture lines of rat somatotropinoma cells (GH3 cells) and primary cultures of pituitary cells derived from normal rats and from human somatotropinomas: 1) The regulation of GH synthesis by IGF and insulin will be examined by studying the hormonal regulation and ontogeny of IGF and insulin receptors. The ability of somatomedins and insulin to regulate GH secretion and mRNA synthesis will be examined using anti-receptor monoclonal antibodies and by measuring GH released into the medium and intracellular GH mRNA levels. 2) The regulation of IGF synthesis in the pituitary gland and brain will be studied using specific RIAs for the IGFs and RNA probes for each of the somatomedins. These studies will delineate a new feedback role for insulin-like growth factors and will greatly expand our understanding of how IGF, insulin and GRF can regulate pituitary function in normal individuals and in patients with diabetes, acromegaly and hypopituitarism.